Characterization and role of Tumor Infiltrating Lymphocytes (TILs) in Cancer Cachexia

• Grant number: 25/04158-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: July 01, 2025
• End date: June 30, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Marilia Cerqueira Leite Seelaender
• Grantee: Bruna Angela Armiliatto Sottili
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cachexia, a severe metabolic syndrome characterized by systemic inflammation and muscle wasting, affects approximately 50% of colorectal cancer (CRC) patients and significantly worsens prognosis. Despite its prevalence, the immunometabolic mechanisms linking cachexia and tumor progression remain poorly understood. Tumor-infiltrating lymphocytes (TILs) play a crucial role in regulating the tumor microenvironment (TME). Alterations in the phenotype, function, and metabolism of TILs in cachectic patients impacts tumor progression and patient outcomes. This study aims to characterize and compare the profile, metabolic state, and functionality of TILs in cachectic and weight-stable CRC patients. We hypothesize that cachectic patients exhibit increased immune exhaustion, altered cytokine profiles, and impaired TIL cytotoxicity driven by metabolic dysfunction. Tumor and blood samples will be collected from 40 CRC patients (20 cachectic and 20 weight-stable controls). TILs will be isolated and analyzed for phenotype (e.g., CD8+, CD4+, regulatory T cells, and NK cells) and immune exhaustion markers (e.g., PD-1, CTLA-4) using flow cytometry. Functional assays will evaluate TIL cytotoxicity and cytokine secretion (e.g., IL-6, TNF-¿, IFN-¿). Metabolic pathways will be assessed using glycolysis and oxidative phosphorylation markers, while single-cell RNA sequencing will elucidate TIL transcriptional profiles. Statistical comparisons will identify differences in immune and metabolic states between groups. By elucidating the immunometabolic characteristics of TILs in CRC-associated cachexia, this study seeks to uncover novel biomarkers and therapeutic targets to mitigate systemic wasting and improve cancer outcomes.